Fused imidazolium derivatives

ABSTRACT

This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof. 
     The novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized in that the 1- and/or 3-position is substituted by an alkyl group etc. having a substituent selected from the group consisting of —ORa, —SRa and the like, have excellent anti-tumor activity and low toxicity and are useful as anticancer agents having wide margins of safety.

TECHNICAL FIELD

This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof.

BACKGROUND OF THE INVENTION

As imidazolium derivatives fused with aryl or heteroaryl ring and having anti-tumor activity, only the 4,9-dioxonaphtho[2,3-d]imidazolium compounds (KP-1, KP-3 and the like) of the following formula have so far been disclosed in Khim. Pharm. Zh., 32(6), 10-11 (1998).

(In the formula, Et and Me respectively represent ethyl and methyl, the same shall apply hereinafter.)

J. Med. Chem., 7(3), 362-364 (1964) discloses a compound having an antimicrobial action in which R¹ and R² of the general formula (I) of the present invention, which will be described later, are both lower alkyl, or one is -lower alkylene-(an aryl which may have one or more substituents) and the other is —CH₃, —(CH₂)₃CH₃ or -phenyl group, or one is -lower alkylene-CO— (an aryl which may have one or more substituents) and the other is —CH₂CH(CH₃)₂ or —(CH₂)₃CH₃, but there is no disclosure on its anti-tumor activity.

Also, 4,9-dioxonaphtho[2,3-d]imidazolium derivatives in which R¹ and R² of the general formula (I) of the present invention are both lower alkyl groups are disclosed in J. Org. Chem. USSR, 1, 1479-85 (1965), JP-A-3-258765 and JP-A-6-59371 and the like. However, there is no disclosure on the medicinal use of these compounds.

British Patent No. 1314881 discloses 1,4-dihydro-1,4-dioxonaphthalene derivatives useful as a herbicide, and JP-B-54-25085 discloses isoquinoline-5,8-dione derivatives useful as a herbicide, respectively. Also, several 1,4-dihydro-1,4-dioxonaphthalene derivatives are commonly known by Zh. Org. Khim., 22(8), 1736-42 (1986), J. Gen. Chem. USSR, 36, 649-652 (1966) and reagent catalogs [Sigma Aldrich Library of Rare Chemicals Structure Index, with update (Aldrich Chemical Company, Inc.) and the like]. However, all of these documents do not disclose on the medicinal use of these compounds.

Imidazole derivatives fused with aryl ring are disclosed in WO 97/30022, J. Med. Chem., 39(7), 1447-1451 (1996) and J. Med. Chem., 7(3), 362-364 (1964).

DISCLOSURE OF THE INVENTION

Creation of an anticancer agent which exhibits excellent anti-tumor activity and also has low toxicity is still in great demand.

The present inventors have conducted intensive studies on anticancer agents having less side effects and found as a result of the efforts that novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized by being substituted at the 1- and/or 3-position with substituted alkyl group etc., exhibit excellent anti-tumor activity and low toxicity, thus they can be useful as anticancer agents having wide margins of safety. In addition, by finding a 2-acylamino-3-amino-1,4-quinone derivative and a fused imidazole derivative useful as their synthetic intermediates and further finding that this synthetic intermediate 2-acylamino-3-amino-1,4-quinone derivative itself also shows low toxicity and excellent anti-tumor activity, the invention has been accomplished.

That is, the invention relates to a fused imidazolium derivative represented by the following general formula (I) and a pharmaceutical composition, particularly an anticancer agent, which comprises this fused imidazolium derivative and a pharmaceutically acceptable carrier.

(Symbols in the formula have the following meanings;

R¹ and R²: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),

group B: —OR^(a), —SR^(a), -prodrug-formed OH, —O-lower alkylene-OR^(a), —O-lower alkylene —O-lower alkylene-OR^(a), —O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-NR^(c)-lower alkylene-NR^(a)R^(b), —OCO—NR^(a)R^(b), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)—SO₂R^(b), —NR^(a)R^(b), —NR^(c)-lower alkylene-NR^(a)R^(b), —N(-lower alkylene-NR^(a)R^(b))₂, -RinD, —NO₂, —CN, -halogen, —CO₂R^(a), —COO⁻, —CONR^(a)R^(b), —CONR^(a)—O—R^(b), —NR^(a)—COR^(b), —NR^(a)—CO—NR^(b)R^(c), —OCOR^(a) and —CO—R^(a),

R^(a), R^(b) and R^(c): the same or different from one another and each represents —H, -lower alkyl, -lower alkylene-RinD or -RinD,

RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),

R³: —H or -(lower alkyl which may have one or more substituents), or R² and R³ may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴ (R⁴: —H or -lower alkyl),

ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, and

X⁻: counter anion, with the proviso that X⁻ does not exist when the substituent —COO⁻ of the group B forms intramolecular salt with imidazolium cation,

with the proviso that compounds having the following combinations of R¹and R² are excluded:

(1) one is -lower alkylene-(aryl which may have one or more substituents) and the other is —CH₃, —(CH₂)₃CH₃ or -phenyl,

(2) one is -lower alkylene-CO-(aryl which may have one or more substituents) and the other is —CH₂CH(CH₃)₂ or —(CH₂)₃CH₃, or

(3) R¹ and R² are both -benzyl, —(CH₂)₂OC₂H₅ or —(CH₂)₂O—COCH₃; the same shall apply hereinafter.)

Also, the invention relates to a 2-acylamino-3-amino-1,4-quinone derivative represented by the following general formula (II) or a salt thereof, which is a synthetic intermediate of the above general formula (I) and has excellent anti-tumor activity by itself too, and to a pharmaceutical composition, particularly an anticancer agent, which contains this compound or a salt thereof and a pharmaceutically acceptable carrier.

(Symbols in the formula have the following meanings;

R¹ and R²: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),

group B: —OR^(a), —SR^(a), -prodrug-formed OH, —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), —O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-NR^(c)-lower alkylene-NR^(a)R^(b), —OCO—NR^(a)R^(b), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)—SO₂R^(b), —NR^(a)R^(b), —NR^(c)-lower alkylene-NR^(a)R^(b), —N(-lower alkylene-NR^(a)R^(b))₂, -RinD, —NO₂, —CN, -halogen, —CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(a)—O—R^(b), —NR^(a)—COR^(b), —NR^(a)—CO—NR^(b)R^(c), —OCOR^(a) and —CO—R^(a),

R^(a), R^(b) and R^(c): the same or different from one another and each represents —H, -lower alkyl, -lower alkylene-RinD or -RinD,

RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),

R³: —H or -(lower alkyl which may have one or more substituents), or R² and R³ may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴ (R⁴: —H or -lower alkyl), and

ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents,

with the proviso that compounds of the following table are excluded;

TABLE 2 (II-E)

Comp X R —R¹ —R² —R³ E-1 CH H —Me —CH₂-(3,4-Cl—Ph) —Me E-2 CH H —CH(Me)₂ —CH₂-(3,4-Cl—Ph) —Me E-3 CH H —CH₂—Ph -(4-MeO—Ph) —Me E-4 CH H —CH₂—Ph -(3-Br—Ph) —Me E-5 CH H —CH₂—Ph —CH₂-(4-F—Ph) —Me E-6 CH H —(CH₂)₂—Ph —CH₂-(4-F—Ph) —Me E-7 CH H —(CH₂)₂—OH —Me —Me E-8 CH H —(CH₂)₂—OH —CH₂—Ph —Me E-9 CH H —(CH₂)₂—OH -(4-MeO—Ph) —Me E-10 CH H —(CH₂)₂—OH -(4-MeO—Ph) —Me E-11 CH H —(CH₂)₂—OH -(3-Br—Ph) —Me E-12 CH H —(CH₂)₂—Cl —CH₂CO₂Et —Me E-13 CH H —CH(Me)—CO₂H —Me —Me E-14 CH H —CH(Me)—CONHMe —Me —Me E-15 CH H —CH(Me)—CONHMe —CH(Me)₂ —Me E-16 CH H —CH(Me)—CONHMe

—Me E-17 CH H —CH(Me)—CONHMe —Me —(CH₂)₂Me E-18 CH H —CH(Me)—CONHMe —Me —CH(Me)₂ E-19 CH H —CH(Me)—CONHOMe —Me —Me E-20 N H —CH(Me)—CONHMe —Me —Me E-21 N Me —CH(Me)—CONHMe —Me —Me E-22 CH H

—Me —Me

(in this table, Comp means compound number, Me means methyl group, Et means ethyl group and Ph means phenyl group, and in the case of a substituted phenyl group, the substituent is shown before Ph together with the substituting position, e.g., 3,4-Cl—Ph represents 3,4-dichlorophenyl, the same shall apply hereinafter).

The compounds shown in Table 2 are commonly known by British Patent No. 1314881 and JP-B-54-25085 in relation to herbicides, Zh. Org. Khim., 22(8), 1736-42 (1986) and J. Gen. Chem. USSR, 36, 649-652 (1966) in relation to their synthesis methods, and by reagent catalogs [Sigma Aldrich Library of Rare Chemicals Structure Index, with update (Aldrich Chemical Company, Inc.) and the like].)

In addition, the invention relates to a fused imidazole derivative represented by the following general formula (III) or a salt thereof, which is a novel synthetic intermediate of the aforementioned general formula (I).

(Symbols in the formula have the following meanings;

R¹: -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B) or -(cycloalkyl having one or more substituents), with the proviso that a lower alkyl group having one or more substituents selected from the group consisting of —NH₂, —NMe₂, —NEt₂, —OH, -halogen and -(phenyl which may be substituted by —Cl, —F, —Me or —OMe) is excluded,

group B: —OR^(a), —SR^(a), -prodrug-formed OH, —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), —O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-NR^(c)-lower alkylene-NR^(a)R^(b), —OCO—NR^(a)R^(b), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)—SO₂R^(b), —NR^(a)R^(b), —NR^(c)-lower alkylene-NR^(a)R^(b), —N(-lower alkylene-NR^(a)R^(b))₂, -RinD, —NO₂, —CN, -halogen, —CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)—O—R^(b), —NR^(a)—COR^(b), —NR^(a)—CO—NR^(b)R^(c), —OCOR^(a) and —CO—R^(a),

R^(a), R^(b) and R^(c): the same or different from one another and each represents —H, -lower alkyl, -lower alkylene-RinD or -RinD,

RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),

R³: —H or -(lower alkyl which may have one or more substituents), and

ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, the same shall apply hereinafter.)

The compounds of general formula (I), (II) and (III) are further described.

According to this description, the term “lower” means a straight or branched form of hydrocarbon chain having from 1 to 6 carbon atoms. As the “lower alkyl”, it is preferably an alkyl group having from 1 to 4 carbon atoms, and its particularly preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl groups. As the “lower alkenyl”, its preferred examples include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. As the “lower alkynyl”, its preferred examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl groups. Also, as the “lower alkylene”, its preferred examples include methylene, ethylene, trimethylene and 2,2-dimethyltrimethylene groups.

The “aryl” means an aromatic hydrocarbon ring group, and its preferred examples include aryl groups having from 6 to 14 carbon atoms, more preferably phenyl, naphthyl and fluorenyl groups. Also, as the “aryl ring” in the ring A, it is a ring which forms the above aryl ring, and its preferred examples include benzene and naphthalene rings.

Examples of the “heteroaryl” include five- or six-membered monocyclic heteroaryl groups containing from 1 to 4 hetero atoms selected from N, S and O and bicyclic heteroaryl groups in which they are fused with a benzene ring or five- or six-membered monocyclic heteroaryl ring, which may be partially saturated. Also, when it contains N atom, it may form N-oxide. In this case, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl groups are preferred as the five- or six-membered monocyclic heteroaryl, and benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl and imidazopyridyl groups are preferred as the bicyclic heteroaryl. As the partially saturated heteroaryl, 1,2,3,4-tetrahydroquinolyl group and the like can be exemplified. Further preferred are furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, benzoimidazolyl, benzodioxonyl and quinolyl groups, and particularly preferred are pyridyl, pyrazinyl and pyrimidinyl groups.

The heteroaryl ring of the ring A is a ring which forms the above heteroaryl group, preferably a five- or six-membered monocyclic heteroaryl ring, and more preferred are thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyridine, pyrazine and pyrimidine rings.

As the “cycloalkyl”, preferred are cycloalkyl groups having from 3 to 10 carbon atoms and particularly preferred are cyclopropyl, cyclopentyl, cyclohexyl and adamantyl groups. As the “cycloalkenyl”, preferred are cycloalkenyl groups having from 3 to 8 carbon atoms and particularly preferred are cyclopentenyl and cyclohexenyl groups.

As the “counter anion”, there is no particular limitation with the proviso that it is a pharmaceutically acceptable anion as a counter anion of imidazolium cation, and its preferred examples include monovalent or divalent anions such as halogen ions, organic sulfonate ions (methanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion and the like), acetate ion, trifluoroacetate ion, carbonate ion, sulfate ion and the like, of which halogen ions are particularly preferred.

As the “halogen”, F, Cl, Br and I atoms can be exemplified, and the “halogen ion” means their ions. The “halogeno lower alkyl” is the aforementioned lower alkyl which is substituted by one or more of the halogen, and is preferably —CF₃.

The “five- to seven-membered saturated heterocyclic ring” is a five- to seven-membered monocyclic saturated heterocyclic ring containing from 1 to 4 hetero atoms selected from N, S and O, or its cross-linked ring. Preferred are tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, quinuclidinyl, piperidyl and morpholinyl groups.

The “-prodrug-formed OH” is a group which formed a reversible prodrug derivative that can be restored to its parent compound (original hydroxy compound) in the living body, and its examples include groups described, e.g., in Prog. Med., 5: 2157-2161 (1985). Its preferred examples include —OCO-(lower alkylene which may have one or more substituents)-COOR (R represents H or lower alkyl, the same shall apply hereinafter), —OCO-(lower alkenylene which may have one or more substituents)-COOR, —OCO-(aryl which may have one or more substituents), —OCO-lower alkylene-o-lower alkylene-COOR, —OCO—CO—R, —OCO-(lower alkyl which may have one or more substituents), —OSO₂-(lower alkylene which may have one or more substituents)-COOR, —O-phthalidyl, 5-methyl-1,3-dioxolen-2-one-4-yl-methyloxy and the like.

As the substituent in the -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkyl which has one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents), it is not particularly limited but is preferably from 1 to 4 substituents selected from the following group C.

Group C: -lower alkyl, -halogen, -halogeno lower alkyl, —OR^(a), —O-lower alkylene-OR^(a), —SR^(a), —NR^(a)R^(b), —NO₂, —CN, —CO₂R^(a), —CO—NR^(a)R^(b), —COR^(a), —NR^(a)—COR^(b), —SO₂NR^(a)R^(b), -lower alkylene-NR^(a)R^(b), -aryl, -lower alkylene-aryl and —OCO—R^(a) (in these formulae, R^(a) and R^(b) are as defined in the foregoing).

Among the group C, more preferred are -lower alkyl, -halogen, -halogeno lower alkyl, —OH, —O-lower alkyl, —O-lower alkylene-OH, —O-lower alkylene-O-lower alkyl, -lower alkylene-NH₂, —NH₂, —NH-lower alkyl, —N (lower alkyl)₂, —CO₂H, —CO₂-lower alkyl, —CO—NH₂, —SO₂—NH₂, —NO₂ and —CN. The same shall apply hereinafter.

As the substituent of the “aryl ring which may have one or more substituents” or “heteroaryl ring which may have one or more substituents” in the ring A, the aforementioned groups of the group C can be cited as preferred examples, and more preferred groups are also the same as described above. Particularly preferred is —NO₂.

Though the substituent the “lower alkyl which may have one or more substituents” of R³ is not particularly limited, it is preferably a substituent of the aforementioned group B, more preferably -halogen, —OR^(a), —SR^(a), —NR^(a)R^(b), —NO₂ or —CN.

In this connection, as the groups shown using R^(a), R^(b) and R^(c) in the aforementioned group B and group C, groups in which R^(a), R^(b) and R^(c) are —H or -lower alkyl are more desirable.

In general formula (I), the term “R² and R³ together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴ (R⁴: —H or -lower alkyl)” means that R² and R³ together form a lower alkylene chain which may be interrupted with O, S or NR⁴ (preferably —(CH₂)₄—, —(CH₂)₂OCH₂— or —(CH₂)₂N(Me)CH₂—), and combined with the adjacent N and C atoms to form a four- to seven-membered hetero ring which is fused with imidazole ring.

Preferred compound of the compound (I) or (II) of the invention is,

(1) a compound in which at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from the group B), -(lower alkenyl having one or more substituents selected from the group B), -(lower alkynyl having one or more substituents selected from the group B), -(cycloalkyl having one or more substituents selected from the group C) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C); RinD is -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(cycloalkyl which may have one or more substituents selected from the group C), -(cycloalkenyl which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) or -(heteroaryl which may have one or more substituents selected from the group C); R³ is —H or -(lower alkyl which may have one or more substituents selected from the group B), or R² and R³ may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴ (R⁴: —H or -lower alkyl); and ring A is aryl ring which may have one or more substituents selected from the group C or heteroaryl ring which may have one or more substituents selected from the group C,

(2) a compound in which at least one of R¹and R² is a lower alkyl having one or more substituents selected from the group B,

(3) a compound in which both of R¹ and R² are the same or different lower alkyl having one or more substituents selected from the group B,

(4) a compound in which at least one of R¹ and R² is a lower alkyl having one or more substituents selected from the group consisting of —OR^(a), —NR^(a)R^(b), —NR^(a)—COR^(b), —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), —SR^(a), —CONR^(a)R^(b), —CN, -(cycloalkyl which may have one or more substituents selected from the group C), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) and -(heteroaryl which may have one or more substituents selected from the group C),

(5) a compound in which at least one of R¹and R² is a lower alkyl having one or more substituents selected from the group consisting of —OR^(a), —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) and -(heteroaryl which may have one or more substituents selected from the group C),

(6) a compound in which at least one of R¹and R² is a lower alkyl substituted by a heteroaryl group selected from furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzoimidazolyl, benzodioxonyl and quinolyl group, which may have one or more substituents selected from the group C,

(7) a compound in which one of R¹ and R² is a lower alkyl substituted by —O-lower alkyl and the other is a lower alkyl substituted by one substituent selected from the group consisting of —O-lower alkylene-O-lower alkyl, —O-lower alkylene-O-lower alkylene-O-lower alkyl, -(aryl which may have one or more substituents selected from the group C), -(heteroaryl which may have one or more substituents selected from the group C) and —O-lower alkyl,

(8) a compound in which at least one of R¹ and R² is a lower alkyl having one substituent selected from the group consisting of -(heteroaryl selected from pyridyl, pyrazinyl and pyrimidinyl, which may have one or more substituents selected from the group C), —O-lower alkylene-O-lower alkyl and —O-lower alkyl,

(9) a compound in which R³ is methyl group,

(10) a compound in which the ring A is benzene ring which may have one or more substituents selected from the group C or a heteroaryl ring selected from thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyridine, pyrazine, pyridazine and pyrimidine ring, which may have one or more substituents selected from the group C,

(11) a compound in which the ring A is benzene ring which may be substituted by —NO₂, or

(12) a compound in which X⁻ is a halogen ion.

Also, another preferred compound of the compound (I) of the invention is a fused imidazolium derivative in which R¹ and R² are the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B′), -(lower alkenyl having one or more substituents selected from group B′), -(lower alkynyl having one or more substituents selected from group B′), -(cycloalkyl which may have one or more substituents selected from group C′), -(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group C′), -(aryl which may have one or more substituents selected from group C′), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C′), -lower alkylene-(aryl which may have one or more substituents selected from group C′), -lower alkylene-CO-(aryl which may have one or more substituents selected from group C′), -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from group B′). -(lower alkenyl having one or more substituents selected from group B′) or -(lower alkynyl having one or more substituents selected from group B′); group B′is —OR^(a), —SR^(a), -prodrug-formed OH, —O-lower alkylene-RinD, —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)—SO₂R^(b), —NR^(a)R^(b), —NR^(c)-lower alkylene-RinD, —N(-lower alkylene-RinD)₂, —NR^(c)-lower alkylene-NR^(a)R^(b), —N(lower alkylene-NR^(a)R^(b))₂, -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C′), -(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group C′), -cycloalkyl, —S-lower alkylene-RinD, —NO₂, —CN, —CO₂R^(a), —CONR^(a)R^(b), —NR^(a)—COR^(b), —OCOR^(a), —CO-lower alkyl and —CO-(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group C′); R^(a), R^(b)and R^(c) are the same or different from one another and each represents —H, -lower alkyl or -RinD; RinD is -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C′), -(aryl which may have one or more substituents selected from group C′) or -(five- or 6-membered monocyclic heteroaryl which may have one or more substituents selected from group C′); group C′is -lower alkyl, -halogen, —OR^(a), —SR^(a), —NR^(a)R^(b), —NO₂, —CN, —CO₂R^(a), —CO—NR^(a)R^(b), —COR^(a), —NR^(a)—COR^(b), and —OCO—R^(a); R³ is —H or -lower alkyl; ring A is benzene ring which may have a substituent selected from the group consisting of -lower alkyl, —OR^(a), —NR^(a)R^(b), —CN, -halogen and —NO₂; and X⁻ is counter anion.

Among compounds (I) of the invention, particularly preferred compounds are 1-[(6-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1,2-dimethyl-4,9-dioxo-3-[(2-tetrahydrofuranyl)methyl]-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1,3-bis(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[3-(1H-4-imidazolyl)propyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-1-[(5-methyl-2-pyrazinyl)methyl]-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 2-methyl-4,9-dioxo-1,3-bis(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[2-(2-methoxyethoxy)ethyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,19-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(3-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(2-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(4-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-hydroxy-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-1-[(6-methoxy-3-pyridyl)methyl]-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-chloro-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-chlorobenzyl)-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-fluorobenzyl)-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium and 1,3-bis(2-methoxyethyl)-2-methyl-5-nitro-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, or tautomers thereof and their salts with halogen ions.

The compound (I) of the invention exists in tautomer forms represented by the following formula due to delocalization of the cation, and these isomers in separated forms or mixtures thereof are included in the invention. The compound mentioned herein as 1H-imidazol-3-ium derivative includes 3H-imidazol-1-ium derivative as its tautomer and mixture of both isomers. In this connection, X⁻ does not exist when the compound (I) has a substituent —COO⁻ and forms intramolecular salt with the imidazolium cation.

In addition to the aforementioned salt with a counter anion, the compound (I) of the invention forms other salts in some cases depending on the kinds of substituents, and these salts are also included in the invention. In addition, the compound (II) or (III) of the invention also forms salts in some cases depending on the kinds of substituents, and these salts are also included in the invention. Though these salts are not particularly limited with the proviso that they are pharmaceutically acceptable salts, acid addition salts with an inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like) and with an organic acid (formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like) can be cited as illustrative examples of acid addition salts, and salts with an inorganic base containing a metal (sodium, potassium, magnesium, calcium, aluminum and the like) or with an organic base (methylamine, ethylamine, ethanolamine, lysine, ornithine and the like) and ammonium salts and the like can be exemplified as salts with bases.

Depending on the kinds of substituents, geometrical isomers and tautomers exist in the compound (I), (II) or (III) of the invention in some cases, and these isomers in separated forms or mixture thereof are included in the invention. Also, since certain compounds of the invention have asymmetric carbon atom, isomers based on the asymmetric carbon atom can exist. The invention includes mixed and separated forms of these optical isomers. Also, compounds of the invention may sometimes form N-oxide depending on the kinds of substituents, and these N-oxide compounds are also included in the invention. In addition, various hydrates and solvates and polymorphic substances of the compound (I), (II) or (III) of the invention are also included in the invention.

Synthesis Methods

The compounds (I), (II) and (III) of the invention can be synthesized easily by using similar methods described in references, e.g., J. Org. Chem. USSR, 1, 1479-85 (1965), J. Med. Chem., 7(3), 362-364 (1964), JP-A-3-258765, or by applying the methods known to those skilled in the art.

In this connection, depending on the kind of functional group, it may sometimes be effective from the viewpoint of synthesis techniques to replace the functional group with an appropriate protecting group, namely a group which can be easily converted into the functional group, at the stage of starting materials or synthetic intermediates. Thereafter, a desired compound can be obtained by removing the protecting group as occasion demands. Examples of such functional groups include a amino group, a hydroxyl group, a carboxyl group and the like and examples of their protecting groups include those which are described in “Protective Groups in Organic Synthesis”, 2nd edition, edited by Greene and Wuts, which may be optionally used depending on the reaction conditions.

The following describes typical Synthesis methods.

(In the formula, R′ means hydrogen, methoxy or halogen group, and H—X means an acid which forms anion (preferably hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, methanesulfonic acid, ethanesulfonic acid and the like). The same shall apply hereinafter.)

Synthesis Method 1

The compound (II) of the invention can be synthesized in the usual procedures by allowing a compound (IV) to react with amines (V). For example, it can be synthesized by applying the methods described in Chem. Pharm. Bull., 44(6), 1181-1187 (1996), Syn. Comm., 27 (12), 2143-2157 (1997), Tetrahedron. Lett., 39(42), 7677-7678 (1998) and the like, and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (benzene and the like) using reaction equivalent amounts of the compounds (IV) and (V), or one of them in an excess amount, if necessary using an appropriate inorganic base (potassium carbonate and the like) or organic base (triethylamine and the like) as an acid capturing agent.

Synthesis Method 2

The compound (I) of the invention can be synthesized in the usual procedures by subjecting the compound (II) of the invention to cyclization and making it into a quaternary salt. For example, the reaction can be carried out by applying the method described in J. Org. Chem. USSR, 1, 1479-85 (1965), and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (e.g., an alcohol solvent) using a reaction equivalent amount or an excess amount of an acid.

Synthesis Method 3

(In the formula, R^(d) and R^(e) are any groups defined in R¹and R². The same shall apply hereinafter.)

Two compounds (IIa) and (IIb) of the invention can be synthesized by hydrolysis of the compound (I) of the invention in the usual procedures. The obtained compounds can also be made into synthetic intermediates of desired compound (I) of the invention by subjecting them to commonly known substituent-modification reactions.

The hydrolysis reaction can be carried out by applying the method described in J. Med. Chem., 7(3), 362-364 (1964) and the like, and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (ethanol and the like) using a reaction equivalent amount or an excess amount of a base. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate can be exemplified.

Synthesis Method 4

The compound (III) of the invention can be synthesized in accordance with the method described in J. Med. Chem., 39(7), 1447-1451 (1996) and the like, by subjecting a compound (VI) to cyclization reaction in the presence of a base such as sodium hydroxide and the like.

Synthesis Method 5

The compound (I) of the invention can be synthesized by allowing the compound (III) of the invention to react with a halide (VII) to make it into a quaternary salt For example, the reaction can be carried out in accordance with the method described in J. Med. Chem., 7(3), 362-364 (1964), preferably in an appropriate inert solvent using reaction equivalent amounts of the compounds (III) and (VII), or one of them in an excess amount, at ambient temperature or under heating, preferably under reflux temperature of the solvent.

In addition to the above Synthesis methods, compounds of the invention can also be synthesized by various commonly known modification methods of substituents. For example, a compound having a substituent containing sulfonyl bond can be synthesized from a compound having sulfide bond or sulfinyl bond by usual oxidation reaction. A N-oxide derivative of a compound having a N atom-containing heteroaryl group (e.g., pyridyl group) as a substituent can be synthesized by usual oxidation reaction. A compound having a carboxylic acid-containing substituent can be synthesized from a compound having ester or amide bond by usual hydrolysis reaction. A compound having an aminoalkyl group-containing substituent can be synthesized from a compound having a halogen-substituted alkyl bond by usual amination reaction. In case that the compounds (II) and (III) of the invention are in free forms, they can be made into salts by usual salt forming reaction as occasion demands.

Synthesis of Material Compounds

Some of the material compounds of the compounds of the invention are novel compounds, and these compounds can be synthesized easily in a similar manner as known material compounds or by using methods commonly known to those skilled in the art. Typical synthesis methods are shown below.

The compound (IV) can be synthesized in accordance with the method described in J. Org. Chem. USSR, 1, 1479-85 (1965) and the like, by a usual acylation reaction in which a compound (VIII) is allowed to react with a reactive carboxylic acid derivative such as an acid halide, acid anhydride and the like.

(In the formula, B¹ represents pyridine ring which may have one or more substituents. The same shall apply hereinafter.)

An aminomethylpyridine derivative (X) can be synthesized by the reduction of a compound (IX) in accordance with the method described in German Patent No. 3726993 (1989) and the like.

The compound (VI) can be synthesized by the amination of a compound (XI) in accordance with the method described in J. Med. Chem., 39(7), 1447-1451 (1996) and the like.

The compound (VIII) can be synthesized by the amination of a compound (XII) in accordance with the method described in J. Het. Chem., 33(1), 113-117 (1996), Syn. Comm., 27(12), 2143-2157 (1997), Tetrahedron. Lett., 39(42), 7677-7678 (1998) and the like.

The compound (IV) can be synthesized by the amidation of the compound (XII). It is advantageous to carry out the reaction by activating a reaction equivalent amount of a compound (XIII) using an appropriate inorganic base (NaH and the like) or organic base (NaOMe and the like) in an appropriate inert solvent (N,N-dimethylformamide (DMF) and the like) and then allowing it to react with a reaction equivalent amount or an excess amount of the compound (XII) at ambient temperature or under heating.

Isolation and purification of the compounds of the invention synthesized in the above described manner are carried out by applying general chemical techniques such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like.

Each form of isomers can be isolated by usual procedures making use of physicochemical differences among isomers. For example, racemic compounds can be converted into optically pure isomers by a conventional optical resolution method [e.g., a method in which they are made into diastereomer salts with a general optically active acid (tartaric acid and the like) and then subjected to optical resolution]. Also, a diastereomer mixture can be separated by fractional crystallization, chromatography and the like. In addition, an optically active compound can also be synthesized by using an appropriate optically active material.

Industrial Applicability

The compounds (I) and (II) of the invention are useful as anticancer agents which have excellent cancer cell growth inhibitory activity, low toxicity and wide margins of safety. Accordingly, the compounds of the invention have the inhibitory activity on growth of tumors, preferably all solid tumors and lymphomas, particularly skin cancer, bladder cancer, breast cancer, uterine cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer and the like, thus they are useful for the treatment thereof. Particularly, they show excellent anti-tumor activity for many kinds of tumor types in a cancer cell growth inhibition test and an in vivo tumor growth inhibition test using a mouse tumor xenograft model, and the activity is superior to those of some existing anticancer agents. Accordingly, they are expected as therapeutic agents for tumor types which show resistance against existing anticancer agents.

Effects of the compounds of the invention were verified by the following tests.

TEST EXAMPLE 1 Cancer Cell Growth Inhibition Test

(Test methods) Cell culture: Cervix cancer HeLaS3 cells or melanoma A375 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (mfd. by GIBCO) supplemented with 10% Fetal Calf Serum (FCS).

Compound evaluation: HeLaS3 cells or A375 cells were added to a gelatin-coated 96 well plate (mfd. by IWAKI) and cultured overnight in DMEM. On the next day, a dimethylsulfoxide (DMSO) solution of test compound was added thereto with varied concentrations, while fixing final concentration of DMSO solution to 0.1%. After incubation for 48 hours, cell growth was evaluated by color reaction with Alamar Blue (mfd. by Biosource).

(Results) The compounds (I) and (II) of the invention satisfactorily inhibited growth of cancer cells, and their IC₅₀ values were 1 μM or less.

In addition, the compounds (I) and (II) of the invention showed similarly excellent cell growth inhibitory activities also for other cancer cells (non-small cell lung cancer (EKVX, HOP-92, NCI-H358, A-549, NCI-H460), breast cancer (MDA-MB-231, MCF7), prostate cancer (PC-3), pancreas cancer (MIA PaCa-2), colon cancer (WiDr), renal cancer (A-498), gastric cancer (MKN28), bladder cancer (UC-14) and fibrosarcoma (HT-1080)).

TEST EXAMPLE 2 In vivo Tumor Growth Inhibition Test

(Test methods) Melanoma A375 cells (2×10⁶ cells) were grafted subcutaneously into the frank of male Balb/c nude mice. When the tumor volume reached 50 to 100 mm³, the test compound was intravenously administered once a day for 2 weeks. Also, saline was intravenously administered to a control group. Tumor diameter was periodically measured with a vernier caliper until the next day of the final administration. The tumor volume was calculated by the following calculation formula.

Tumor volume (mm³)=½×[a shorter diameter (mm)]²×a longer diameter (mm)

(Results) In this test, the compounds (I) and (II) of the invention satisfactorily inhibited tumor growth, e.g., the compounds of Examples 4, 37, 118, 121, 148, 154, 180 and 182 showed 50% or more inhibition of tumor growth compared to the control group at a dose of 0.3 or 1 mg/kg.

The compounds of the invention showed similarly excellent anti-tumor activity also in an animal model transplanted with other cancer cells (prostate cancer (PC-3) or non-small cell lung cancer (NCI-H358, A-549 and NCI-H460)).

TEST EXAMPLE 3 Mouse Single Administration Toxicity Test

(Test methods) The compounds of the invention were administered by single intravenous administration to Balb/C mice, and the presence of mortal case during the observation period of 2 weeks was evaluated.

(Results) Mortal case was not found by 3 mg/kg single administration of each of the compounds of Examples 4, 9, 35, 37, 52, 72, 121, 133, 148, 154, 158, 180, 182, 184, 185, 186, 192 and 197 of the invention. On the other hand, all of respective 2 cases died by 3 mg/kg single administration of KP-1 and KP-3 disclosed in a prior report, Khim. Pharm. Zh., 32(6), 10-11 (1998). Thus, it was shown that the compounds of the invention have low toxicity in comparison with the prior reported compounds.

Accordingly, since the compounds (I) and (II) of the invention showed excellent anti-tumor activities against many kinds of tumor types with low toxicity, it was shown that they are useful as anticancer agents having good therapeutic profiles.

The pharmaceutical composition of the invention can be prepared by a generally used method using one or two or more of the compounds represented by the general formula (I) or (II) and pharmaceutically acceptable carriers (drug carriers, fillers and the like). Its administration may be either oral administration by tablets, pills, capsules, granules, powders, solutions, inhalations and the like, or parenteral administration by intravenous injection, intramuscular injection, and the like, suppositories, eye drops, ophthalmic ointments, percutaneous solutions, ointments, percutaneous adhesive preparations, transmucosal solutions, transmucosal adhesive preparations and the like.

The solid composition for use in the oral administration according to the present invention is used in the form of tablets, powders, granules and the like. In such a solid composition, one or more active substances are mixed with at least one inert filler such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate and the like. In accordance with the usual procedures, the composition may contain inert additives such as lubricants (magnesium stearate and the like) and disintegrating agents (sodium carboxymethylstarch and the like) and solubilization assisting agent. If necessary, tablets or pills may be coated with a sugar or a gastric or enteric coating agent.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent conventionally employed, e.g., purified water or ethanol. In addition to the inert diluent, this composition may further contain an auxiliary agent such as a solubilizing agent, a moistening agent, a suspending agent and the like, as well as sweeteners, flavors, aromatics and preservatives.

The injections for parenteral administration include a sterile aqueous or non-aqueous solution, a suspension and an emulsion. Examples of the aqueous solution include distilled water for injection and saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable (oils olive oil and the like), alcohols (ethanol and the like), polysorbate 80 (trade name) and the like. Such a composition may further contain a tonicity agent, a preservative, a moistening agent, an emulsifier, a dispersing agent, a stabilizer and a solubilization assisting agent. These compositions are sterilized, e.g., by filtration through a bacteria retaining filter, blending of a germicide or irradiation. Alternatively, they may be used by firstly making into sterile solid compositions and then dissolving or suspending them in sterile water or a sterile solvent for injection use prior to their use.

In the case of oral administration, suitable daily dose is usually about 0.001 to 50 mg/kg, preferably about 0.01 to 30 mg/kg, and in the case of intravenous administration, the daily dose is usually about 0.0001 to 10 mg/kg, preferably about 0.001 to 3 mg/kg, and the daily dose is divided into 1 to several doses per day. The dose may be appropriately determined for each case, depending on conditions, age, sex and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The following describes the invention further in detail based on examples. The compounds of the invention are not limited to the compounds described in the following examples. In this connection, Synthesis examples of material compounds of the compounds of the invention are shown in Reference Examples.

REFERENCE EXAMPLE 1

Saturated aqueous ammonia (17 ml) and Raney nickel (3.0 g) were added to a solution of 3-cyano-2-(dimethylamino)pyridine (2.45 g) in ethanol (50 ml) and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere of 1 atmospheric pressure. After absorption of 760 ml of hydrogen, the catalyst was removed by filtration. By concentrating the mother liquid, 3-(aminomethyl)-2-(dimethylamino)pyridine (2.61 g) was obtained as a yellow oil.

REFERENCE EXAMPLE 2

A few drops of concentrated sulfuric acid was added to a solution of 2-chloro-3-[(2-methoxyethyl)amino]-1,4-naphthoquinone (33 g) in acetic anhydride (100 ml) and the mixture was stirred at 45° C. for 1 hour. By adding ethanol (100 ml) to the reaction solution, excess acetic anhydride was esterified. After cooling, ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from diethyl ether to give N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (29 g) as a yellow powder.

REFERENCE EXAMPLE 3

2-Methoxyethylamine (0.8 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)acetamide (1.0 g) in benzene (20 ml) and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.87 g) as a red powder.

REFERENCE EXAMPLE 4

2-(Aminomethyl)pyrazine (3.2 g) and diisopropylethylamine (5.8 ml) were added to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (3.0 g) in benzene (90 ml) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-[(2-pyrazinylmethyl)amino]naphthalene (0.23 g) as a light brown powder.

REFERENCE EXAMPLE 5

2-Chloroacetyl chloride (3.3 ml) was added to a solution of 2-chloro-1,4-dihydro-3-methylamino-1,4-dioxonaphthalene (2.2 g) in 1,4-dioxane (30 ml) and the mixture was stirred under reflux for 14 hours. After cooling of the reaction solution, the solvent was evaporated. Ethanol was added to the residue and the resulting precipitate was collected by filtration. The obtained solid was recrystallized from ethanol to give 2-chloro-N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-methylacetamide (2.6 g) as a yellow powder.

REFERENCE EXAMPLE 6

NaH (440 mg) was added to a solution of 2-oxopiperidine (1.0 g) in DMF (20 ml) and the mixture was stirred at room temperature for 30 minutes. This solution was added in a single portion to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (6.9 g) in DMF (150 ml) and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into saturated aqueous ammonia and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:10 solution) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-(2-oxopiperidino)naphthalene (0.49 g) as a light brown powder.

REFERENCE EXAMPLE 7

2-Methoxyethylamine (1.6 ml) was added to a solution of methyl 4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (2.4 g) in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 27 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with chloroform) to give methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.5 g) as a yellow powder.

REFERENCE EXAMPLE 8

Five drops of concentrated sulfuric acid was added to a solution of methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.2 g) in acetic anhydride (20 ml) and the mixture was stirred at room temperature for 1 hour. Methanol (20 ml) was gradually added to the reaction solution and then the solvent was evaporated. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish brown powder.

The compounds of Reference Examples 9 to 11 shown in Table 3 were obtained in a similar manner to that described in Reference Example 1, and the compound of Reference Example 12 shown in Table 4 in a similar manner to that described in Reference Example 2, the compounds of Reference Examples 13 to 15 shown in Table 4 in a similar manner to that described in Reference Example 3 and the compound of Reference Example 16 shown in Table 4 in a similar manner to that described in Reference Example 5.

EXAMPLE 1

2 M Sodium hydroxide aqueous solution (0.9 ml) was added to a solution of N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.5 g) in ethanol (10 ml) and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was collected by filtration and washed with ethanol to give 1-(2-methoxyethyl)-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazole (0.58 g) as a light orange powder.

EXAMPLE 2

Benzylamine (0.5 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.5 g) in benzene (15 ml) and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate-hexane to give N-(3-benzylamino-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.51 g) as a red powder.

EXAMPLE 3

80% 3-chloroperbenzoic acid (0.6 g) was added to a solution of N-(2-methoxyethyl)-N-[3-(3-pyridylmethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.95 g) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform-methanol-saturated aqueous ammonia 10:1:0.1 solution) to give 3-[({3-[N-acetyl-N-(2-methoxyethyl)]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}amino)methyl]pyridine 1-oxide (0.84 g) as a brown amorphous solid.

EXAMPLE 4

1 M Sodium hydroxide aqueous solution (5.0 ml) was added to a solution of 1-(2-methoxyethyl)-2-methyl-3-(4-pyridylmethyl)-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride monohydrochloride (1.1 g) in ethanol (30 ml) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (fraction A: elution with ethyl acetate-hexane 1:1 solution, fraction B: elution with ethyl acetate). The fraction A was crystallized from diethyl ether to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-N-(4-pyridylmethyl)acetamide (0.2 g) as a red powder. In this connection, the fraction B was crystallized from ethyl acetate to give a yellow powder (0.31 g) which was found to be the same compound, N-(2-methoxyethyl)-N-[3-(4-pyridylmethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide that will be described later in Example 37.

EXAMPLE 5

80% 3-chloroperbenzoic acid (0.78 g) was added to a solution of N-methyl-N-{3-[2-(methylsulfinyl)ethyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}acetamide (0.52 g) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform-methanol 50:1 solution) to give N-methyl-N-{3-[2-(methylsulfonyl)ethyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}acetamide (0.39 g) as an orange amorphous solid.

EXAMPLE 6

4 M hydrogen chloride/ethyl acetate solution (3 ml) was added to a suspension of N-[3-(2-Hydroxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.4 g) in ethanol (3 ml) and the mixture was stirred at 45° C. for 1 hour. After cooling, the resulting precipitate was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from ethanol-ethyl acetate to give 1-(2-hydroxyethyl)-2,3-dimethyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.28 g) as a colorless powder.

EXAMPLE 7

Benzyl bromide (1.9 ml) was added to a solution of 1-isopropyl-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazole (0.8 g) in acetonitrile (20 ml) and the mixture was stirred under reflux for 6 hours. After cooling, the resulting precipitate was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from methanol to give 1-benzyl-3-isopropyl-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium bromide (0.47 g) as a yellow powder.

EXAMPLE 8

By the similar method of Example 6, 1-(2-hydroxy-3-pyridyl)methyl-3-(2-methoxyethyl)-2-methyl-4,19-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.39 g) was obtained as a light brown powder from N-(2-methoxyethyl)-N-{3-[(2-methoxy-3-pyridyl)methyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}acetamide (0.49 g).

EXAMPLE 9

4 M Hydrogen chloride/ethyl acetate solution (10 ml) was added to a solution of N-{3-[(6-chloro-3-pyridyl)methyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}-N-(2-methoxyethyl)acetamide (0.8 g) in ethanol (10 ml) and the mixture was stirred at room temperature for 1 day. The solvent was evaporated and the residue was collected by filtration and washed with ethyl acetate to give 1-[(6-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.82 g) as a light yellow powder.

EXAMPLE 10

2 M Dimethylamine/tetrahydrofuran solution (3.0 ml) was added to a solution of 2-chloro-N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.5 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to give N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methyl-2-(dimethylamino)acetamide (0.19 g) as a brown powder.

EXAMPLE 11

2-Methoxyethylamine (0.15 ml) was added to a solution of methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 6.5 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with hexane-ethyl acetate 50:1 solution) to give methyl 5-[N-acetyl-N-(2-methoxyethyl)amino]-4,7-dihydro-6-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (0.39 g) as a reddish purple oil.

EXAMPLE 12

4 M Hydrogen chloride/ethyl acetate solution (2.5 ml) was added to a suspension of 3-{[3-(N-acetyl-N-methyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]amino}propionamide (0.32 g) in methanol (30 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was stirred in ethanol with heating. After cooling, the resulting precipitate was collected by filtration and washed with ethanol to give 1-(2-carboxyethyl)-4,9-dihydro-2,3-dimethyl-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.15 g) as a colorless powder.

In a similar manner to those described in the above Examples 1 to 9, the Example compounds described in Tables 6 to 20 were obtained.

Structural formula and physicochemical properties of the reference example compounds are shown in Tables 3 to 5, and those of the Example compounds in Tables 6 to 20. In addition, the compounds having the chemical structures described in Tables 21 to 27 can be easily synthesized by almost the same methods described in the above Examples or the aforementioned processes, or by applying thereto slight modifications which are obvious to those skilled in the art.

Abbreviations in the tables respectively indicate as follows, Ref: reference example; Ex: Example; Co: compound number; Sal; salt; Sy: synthesis method (each numeral indicates the example number, showing that the compound was synthesized by the same method of this example); -: does not exist; Dat: physicochemical properties {F: FAB-MS (M)⁺; F′: FAB-MS (M)⁻; F+: FAB-MS (M+H)⁺; F−; FAB-MS (M−H)⁻; E: EI-MS (M)⁺; N1: ¹H-NMR (DMSO-d₆, TMS internal standard) characteristic peaks δ ppm}; i-Pr: isopropyl; c-Pr: cyclopropyl; Ad: 1-adamantyl; Ac: acetyl; Bn: benzyl; Pipe: piperidino; Morp: morpholino; Py2: 2-pyridyl; Py3: 3-pyridyl; Py4: 4-pyridyl; Th: 2-thienyl; Fu: 2-furyl; Thf: 2-tetrahydrofuranyl; Pyr: 2-pyrazinyl; 5-MePyr: 5-methyl-2-pyrazinyl; Pym: 4-pyrimidinyl; Qu: 3-quinolyl; Dio: 4-benzodioxolyl; Im: 4-imidazolyl; Bim: 2-benzoimidazolyl; and In: 2-indolyl. In this connection, the numeral before each substituent indicates its substitution position, e.g., 3,4-Cl means that —Cl is substituted at the 3- and 4-positions respectively.

TABLE 3 (Xa)

Ref B¹ —R^(f) Dat 1 Py3 2-NMe₂ F+: 152 9 Py3 6-NMe₂ F+: 152 10 Py4 2-NMe₂ F+: 152 11 Py3 2-OMe E: 138

TABLE 4 (IVa) or (VIa) or (VIIIa)

Ref —R^(g) —R^(h) R² Dat  2 —Cl —Ac —(CH₂)₂OMe N1: 1.88(3H, s), 2.99(3H, s), 3.3- 3.9(4H, m), 7.9-8.2(4H, m)  3 —NH—(CH₂)₂OMe —Ac —H F+: 289  4 —Cl —H —CH₂Pyr F′: 299  5 —Cl —COCH₂Cl —Me F: 298  6 —Cl —CO(CH₂)₄— F+: 290 12 —Cl —Ac —CH₂Pyr F′: 341 13 —NH—CH₂(Py3) —Ac —H F+: 322 14 —NH—CH₂(Py4) —Ac —H F+: 322 15 —NH—CH₂(Pyr) —Ac —H F+: 323 16 —Cl —COCH₂OMe —Me F+: 294

TABLE 5 (IVb) or (VIIIb)

Ref R^(h) R² Dat 7 —H —(CH₂)₂OMe F+: 296 8 —Ac —(CH₂)₂OMe F+: 338

TABLE 6 (IIIa)

Ex. —R¹ Dat  1 —(CH₂)₂OMe F+: 271 13 —CH₂(Py3) F+: 304 14 —CH₂(Py4) F+: 304 15 —CH₂(Pyr) F+: 305

TABLE 7 (IIc)

Ex —R^(i) Sy Dat  2 —H — F+: 379 N1: 1.34(3H, br), 3.06(3H, s), 3.1-3.8(4H, m), 4.5-4.8(2H, m), 7.2- 7.4(5H, m), 7.77(1H, dt), 7.85(1H, dt), 7.93(1H, br), 7.98(1H, d), 8.03(1H, d) 16 2-Cl 2 F+: 413 17 3-Cl 2 F+: 413 18 4-Cl 2 F+: 413 N1: 1.39(3H, br), 3.06(3H, s), 3.1-3.4(2H, m), 3.4-3.5(1H, m), 3.6- 3.9(1H, m), 4.5-4.8(2H, m), 7.27(2H, d), 7.38(2H, d), 7.7-8.1(4H, m) 19 3,4-Cl 2 F: 447 20 2-OMe 2 F+: 409 21 3-OMe 2 F+: 409 22 4-OMe 2 F+: 409 23 4-Ph 2 F+: 455 24 2-CN 2 F+: 404 25 3-CN 2 F+: 404 26 4-CN 2 F+: 404 27 4-SO₂NH₂ 2 F+: 458 28 4-CF₃ 2 F+: 447 29 4-F 2 F+: 397 N1: 1.40(3H, br), 3.06(3H, s), 3.1-3.6(3H, m), 3.79(1H, br), 4.5-4.8 (2H, m), 7.1-7.2(2H, m), 7.2-7.5(2H, m), 7.7-8.2(4H, m) 30 4-Br 2 F+: 457, 459 31 3-CH₂NH₂ 2 F+: 408 32 4-CH₂NH₂ 2 F: 407 33 3-NO₂ 2 F+: 424 34 4-NO₂ 2 F+: 424 N1: 1.39(3H, br), 3.07(3H, s), 3.1-3.6(3H, m), 3.6-3.9(1H, m), 4.6-5.0(2H, m), 7.54(2H, d), 7.7-8.2(5H, m), 8.19(2H, d)

TABLE 8 (IId)

Ex B¹ —R^(f) Sy Dat  3 Py3 1-oxide — F+: 396 35 Py3 —H 2 F+: 380 N1: 1.40(3H, s), 3.06(3H, s), 3.1-3.8(4H, m), 4.6-4.8(2H, m), 7.34 (1H, dd), 7.6-8.1(6H, m), 8.4-8.5(2H, m) 36 Py2 —H 2 F+: 380 N1: 1.62(3H, s), 3.06(3H, s), 3.2-3.9(4H, m), 4.5-5.0(4H, m), 7.2-7.5(2H, m), 7.7-8.2(6H, m), 8.54(1H, d) 37 Py4 —H 2 F+: 380 N1: 1.38(1H, br), 3.07(3H, s), 3.1-3.8(4H, m), 4.6-4.8(2H, m), 7.26 (2H, d), 7.77(1H, dt), 7.85(1H, dt), 7.95(1H, d), 8.01(1H, d), 8.48 (2H, d) 38 Py3 2-Cl 2 F+: 414 N1: 1.49(3H, s), 3.07(3H, s), 3.1-3.4(2H, m), 3.4-3.6(1H, m), 3.6-3.8(1H, m), 4.6-4.9(2H, m), 7.3-7.5(1H, m), 7.7-8.2(6H, m) 39 Py3 6-Cl 2 F+: 414 N1: 1.47(3H, br), 3.07(3H, s), 3.1-3.6(3H, m), 3.6-4.0(1H, m), 4.6- 4.9(2H, m), 7.48(1H, d), 7.6-8.1(6H, m), 8.34(1H, d) 40 Py3 2-OMe 2 F+: 410 41 Py3 6-OMe 2 F+: 410 N1: 1.49(3H, s), 3.07(3H, s), 3.1-3.5(3H, m), 3.6-3.9(4H, m), 4.5-4.8(2H, m), 6.79(1H, d), 7.5-7.7(1H, m), 7.7-8.2(5H, m) 42 Py3 2-NMe₂ 2 F+: 423 43 Py3 6-NMe₂ 2 F+: 423 44 Py3 5-Me 2 F+: 394 45 Py3 6-Me 2 F: 393 46 Py3 6-CF₃ 2 F+: 448 47 Py4 2-Cl 2 F+: 414 N1: 1.48(3H, br), 3.09(3H, s), 3.1-3.6(3H, m), 3.6-3.9(1H, m), 4.5- 5.0(2H, m), 7.33(1H, d), 7.45(1H, s), 7.6-8.2(5H, m), 8.34(1H, d) 48 Py4 2-NMe₂ 2 F+: 423 49 Py4 2-OMe 2 F+: 410

TABLE 9 (IIe)

Ex —R¹ —R² Sy Dat  4 —(CH₂)₂OMe —CH₂(Py4) — F+: 380 N1: 1.19(3H, s), 3.26(3H, s), 3.47(4H, br), 4.27(1H, d), 4.81(1H, d), 7.10(1H, br), 7.35 (2H, d), 7.74(1H, dt), 7.82(1H, dt), 7.92 (1H, d), 7.98(1H, d), 8.41(2H, d) 50 —(CH₂)₂OMe —(CH₂)₂OMe 2 N1: 1.83(3H, s), 3.0-3.8(14H, m), 6.9-7.1 (1H, m), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 51 —(CH₂)₂OMe —Bn 2 N1: 1.88(3H, s), 3.23(3H, s), 3.3-3.5(4H, m), 4.4-4.7(2H, m), 6.91(1H, br), 7.1-7.4 (5H, m), 7.6-8.1 (4H, m) 52 —(CH₂)₂OMe —CH₂(Py3) 4 F+: 380 N1: 1.87(3H, s), 3.25(3H, s), 3.4-3.6(4H, m), 4.31(1H, d), 4.81(1H, d), 7.08(1H, br), 7.23(1H, dd), 7.6-7.8(2H, m), 7.81(1H, t), 7.88(1H, d), 7.98(1H, d), 8.37(1H, d), 8.45(1H, s) 53 —Bn —Bn 2 F+: 411 54 —CH₂(Py4) —Bn 2 F+: 412 55 —CH₂(Py3) —Bn 2 F+: 412 56 —(CH₂)₂Ph —(CH₂)₂OMe 2 F+: 393 57 —CH₂Th —(CH₂)₂OMe 2 F+: 387 58 —CH₂Fu —(CH₂)₂OMe 2 F+: 369 59 —CH₂Pyr —(CH₂)₂OMe 2 F+: 381 N1: 1.60(3H, s), 3.07(3H, s), 3.2-3.8(4H, m), 4.5-5.3(2H, m), 7.5-8.2(5H, m), 8.5- 8.8(3H, m) 60 —CH₂Qu —(CH₂)₂OMe 2 F+: 430 61 —(CH₂)₂(Py2) —(CH₂)₂OMe 2 F+: 394 62 —(CH₂)₂(Py3) —(CH₂)₂OMe 2 E: 393 63 —(CH₂)₂(Py4) —(CH₂)₂OMe 2 F+: 394 64 —(CH₂)₂In —(CH₂)₂OMe 2 F+: 432 65 —CH₂Dio —(CH₂)₂OMe 2 F+: 423 66 —(CH₂)₃Im —(CH₂)₂OMe 2 F+: 397 67 —(CH₂)₂Im —(CH₂)₂OMe 2 F+: 383 68 —CH₂Bim —(CH₂)₂OMe 2 F+: 419 69 —(CH₂)₂O(CH₂)₂NH₂ —(CH₂)₂OMe 2 F+: 376 70 —(CH₂)₅NH₂ —(CH₂)₂OMe 2 F+: 374 71 —(CH₂)₂O(CH₂)₂—O(CH₂)₂NH₂ —(CH₂)₂OMe 2 F+: 420

TABLE 10 (IIf)

Ex —B Sy Dat  5 —SO₂Me — F+: 351 72 —OMe 2 F+: 303 N1: 1.83(3H, s), 2.92(3H, s), 3.29(3H, s), 3.4-3.7(4H, m), 7.11(1H, br), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 73 —OPh 2 N1: 1.83(3H, s), 2.93(3H, s), 3.6-3.9(2H, m), 4.21 (2H, t), 6.8-7.1 (3H, m), 7.2-7.5(3H, m), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 74 —OBn 2 N1: 2.89(3H, s), 3.90(2H, t), 4.19(3H, s), 4.45(2H, s), 4.89(2H, t), 7.1-7.5(5H, m), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 75 —NMe₂ 2 F+: 316 N1: 1.83(3H, s), 2.18(6H, s), 2.4-2.6(2H, m), 2.94(3H, s), 3.2-3.5 (2H, m), 7.14(1H, t), 7.7-7.9(2H, m), 7.9-8.1 (2H, m) 76 —OEt 2 F+: 317 N1: 1.10(3H, t), 1.82(3H, s), 2.92(3H, s), 3.3-3.7(6H, m), 7.09(1H, br), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 77 —OPr 2 F+: 331 N1: 0.85(3H, t), 1.4-1.6(2H, m), 1.83(3H, s), 2.92(3H, s), 3.37(2H, t), 3.4-3.7(4H, m), 7.08(1H, br), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 78 —O(i-Pr) 2 F+: 331 N1: 1.07(6H, d), 1.82(3H, s), 2.92(3H, s), 3.4-3.7(5H, m), 7.08(1H, br), 7.7-7.9(2H, m), 7.9-8.1(2H, m) 79 —O(CH₂)₂NH₂ 2 F+: 332 80 —OCH₂(Py3) 2 F+: 413 N1: 1.79(3H, s), 2.90(3H, s), 3.5-3.8(4H, m), 4.55(2H, s), 7.1-7.3 (1H, m), 7.2-7.5(1H, m), 7.7-7.9(3H, m), 7.9-8.1 (2H, m), 8.4-8.6 (2H, m) 81 —SMe 2 F+: 319 82 —NEt₂ 2 F+: 344 83 —N(i-Pr)₂ 2 F+: 372 84 -Pipe 2 F+: 356 85 -Morp 2 F+: 358 86 —NHAc 2 F+: 330 N1: 1.81(6H, s), 2.90(3H, s), 3.2-3.7(4H, m), 7.36(1H, br), 7.7-8.2 (5H, m) 87 —OCONHPh 2 F+: 408 88 —CONH₂ 2 F+: 316 89 —CN 2 F+: 298 90 —O(CH₂)₂OMe 2 F+: 347

TABLE 11 (IIe)

Ex —R¹ —R² Sy Dat  91 —(CH₂)₃OMe —Me 2 N1: 1.7-2.0(5H, m), 2.92(3H, s), 3.25(3H, s), 3.3-3.6(4H, m), 7.2-7.5(1H, m), 7.6-8.2(4H, m)  92 —(CH₂)₃NMe₂ —Me 2 F+: 330  93 —CH₂(Py2) —Me 2 F+: 336 N1: 1.5-2.2(3H, m), 2.7-3.0(3H, m), 4.5-5.0 (2H, m), 7.2-7.5(2H, m), 7.6-8.3(6H, m), 8.4- 8.7(1H, m)  94 —CH₂(Py3) —Me 2 F+: 336  95 —CH₂(Py4) —Me 2 F+: 336  96 —CH₂CF₃ —Me 2 F+: 327  97 —CH₂Thf —Me 2 F+: 329  98 —CH₂CONH₂ —Me 2 F+: 302  99 —CH₂CN —Me 2 F+: 284 100

—Me 2 F+: 418 101

—Me 2 F′: 399 102

—Me 2 F+: 357 103 —CH(Me)Ph —(CH₂)₂OMe 2 F+: 375 104 —CH₂Pym —(CH₂)₂OMe 2 F+: 381 N1: 1.61 (3H, s), 3.08(3H, s), 3.2-3.9(4H, m), 4.6-5.0(2H, m), 7.4-7.6(1H, m), 7.7-8.1(5H, m), 8.75(1H, d), 9.12(1H, d) 105 —(CH₂)₂OMe —CH₂Pyr 2 F+: 381 N1: 1.88(3H, s), 3.26(3H, s), 3.4-3.9(4H, m), 4.3-5.3(2H, m), 7.6-8.1(5H, m), 8.3-8.6(2H, m), 8.79(1H, d) 106 —CH₂(5-MePyr) —(CH₂)₂OMe 2 F+: 395 N1: 1.61(3H, s), 2.47(3H, s), 3.07(3H, s), 3.2-3.8(4H, m), 4.6-5.0(2H, m), 7.7-8.1(5H, m), 8.4-8.6(2H, m)

TABLE 12 Ex —R¹ —R² Sy Dat 107 —CH₂Pyr —CH₂Pyr 2 F+: 415 N1: 1.72(3H,s), 4.3-5.3(4H,m), 7.6-8.1 (4H,m), 8.2-8.7(5H,m), 8.69(1H,s), 8.79 (1H,s) 108 —CH₂(Py4) —CH₂Pyr 2 F+: 414 N1: 1.58(3H,br), 4.2-5.1(4H,m), 7.29(2H, d), 7.6-8.1(4H,m), 8.28(1H,s), 8.3-8.7(4 H,m), 8.78(1H,d) 109 —(CH₂)₁₇Me —(CH₂)₂OMe 2 F+: 541 110 —CH₂Ad —(CH₂)₂OMe 2 F: 437 111 —CH₂CHPh₂ —(CH₂)₂OMe 2 F: 469 112 —(CH₂)₂O(CH₂)₂OMe —(CH₂)₂OMe 2 F: 391 N1: 1.84(3H,s), 3.0-3.9(18H,m), 6.9-7.2 (1H,m), 7.7-7.9(2H,m), 7.9-8.1 (2H,m) 113 —(CH₂)₂O(CH₂)₂O— —(CH₂)₂OMe 2 F: 435 (CH₂)₂OMe 114 —(CH₂)₂O(4-BnO-Ph) —(CH₂)₂OMe 2 F: 515

TABLE 13 (IIg)

Ex A —R² —R³ Sy Dat 10

—Me —CH₂NMe₂ — F+: 346 11

—(CH₂)₂OMe —Me — F+: 411 115

—Me —CH₂Cl 2 F+: 337 116

—Me —CH₂OMe 2 F+: 333 117

—(CH₂)₄— 2 F+: 329

TABLE 14 (Ia)

Ex —B Sal Sy Dat 6 —OH — — F−: 270 N1: 2.90(3H, s), 3.8(2H, br), 4.17(3H, s), 4,74(2H, t), 7.9- 8.2(4H, m) 118 —OMe — 6 F: 285 N1: 2.89(3H, s), 3.25(3H, s), 3.77(2H, t), 4.20(3H, s), 4.8- 5.0(2H, m), 7.9-8.3(4H, m) 119 —OPh — 6 F−: 346 N1: 3.01(3H, s), 4.21(3H, s), 4.43(2H, t), 5.13(2H, t), 6.8- 7.0(3H, m), 7.2-7.4(2H, m), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 120 —OBn — 6 F−: 360 N1: 2.89(3H, s), 3.90(2H, t), 4.19(3H, s), 4.45(2H, s), 4.89 (2H, t), 7.1-7.5(5H, m), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 121 —NMe₂ HCl 6 F: 298 N1: 2.8-3.0(6H, m), 3.02(3H, s), 3.5-3.8(2H, m), 4.16(3H, s), 5.0-5.2(2H, m), 7.9-8.1(2H, m), 8.1-8.3(2H, m), 11.2- 11.5(1H, br) 122 —OEt — 6 F: 299 N1: 1.06(3H, t), 2.89(3H, s), 3.44(2H, q), 3.80(2H, t), 4.20 (3H, s), 4.86(2H, t), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 123 —OPr — 6 F: 313 N1: 0.80(3H, t), 1.3-1.6(2H, m), 2.90(3H, s), 3.35(2H, t), 3.80(2H, t), 4.20(3H, s), 4.87(2H, t), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 124 —O(i-Pr) — 6 F: 313 N1: 1.02(6H, d), 2.89(3H, s), 3.4-3.7(1H, m), 3.79(2H, t), 4.21(3H, s), 4.83(2H, t), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 125 —O(CH₂)₂NH₂ HCl 6 F: 314 126 —OCH₂(Py3) HCl 6 F: 362 N1: 2.90(3H, s), 3.98(2H, t), 4.21(3H, s), 4.68(2H, s), 4.95 (2H, t), 7.8-8.1(3H, m), 8.1-8.4(3H, m), 8.6-8.9(2H, m) 127 —SMe — 6 F: 301 128 —SO₂Me — 6 F: 333 129 —NEt₂ HCl 6 E: 326 130 —N(i-Pr)₂ HCl 6 E: 354 131 -Pipe HCl 6 E: 338 132 -Morp HCl 6 E: 340

TABLE 15 (Ib)

Ex —R¹ Sal Sy Dat 133 —(CH₂)₂NHAc — 6 F: 312 N1: 1.76(3H, s), 2.86(3H, s), 3.4-3.7(2H, m), 4.18(3H, s), 4.69(2H, t), 7.9-8.1(2H, m), 8.1- 8.3(2H, m), 8.34(1H, t) 134 —(CH₂)₂OCONHPh — 6 F: 390 135 —(CH₂)₃OMe — 6 F: 299 N1: 2.0-2.2(2H, m), 2.88(3H, s), 3.24(3H, s), 3.42(2H, t), 4.18(3H, s), 4.69(2H, t), 7.9-8.1 (2H, m), 8.1-8.3(2H, m) 136 —(CH₂)₃NMe₂ HCl 6 F: 312 137 —CH₂(Py2) HCl 6 F: 318 N1: 2.96(3H, s), 4.25(3H, s), 6.14(2H, s), 7.3- 7.6(1H, m), 7.72(1H, d), 7.8-8.3(5H, m), 8.53(1H, d) 138 —CH₂(Py3) HCl 6 F: 318 139 —CH₂(Py4) HCl 6 F: 318 140 —CH₂CF₃ — 6 F: 309 141 —(CH₂)₂CONH₂ — 6 F: 298 142 —(CH₂)₂CN — 6 F: 280 143 —(CH₂)₂O(CH₂)₂OMe — 6 F: 329 144 —CH₂Thf — 6 F: 311 145 —CH₂CONH₂ — 6 F: 284 146 —CH₂CN — 6 F: 266

TABLE 16 (Ic)

Ex —R¹ —R² X Sal Sy Dat 7 —Bn —i-Pr Br — — F: 345 N1: 1.67(6H, d), 2.95(3H, s), 5.44(1H, br), 6.01(2H, s), 7.3-7.5(5H, m), 7.9-8.3(4H, m) 147 —Bn —(CH₂)₂OH Cl — 6 F−: 346 N1: 2.88(3H, s), 3.86(2H, t), 4.75(2H, t), 6.02 (2H, s), 7.3-7.5(5H, m), 7.9-8.3(4H, m) 148 —(CH₂)₂OMe —(CH₂)₂OMe Cl — 6 F−: 328 N1: 2.89(3H, s), 3.24(6H, s), 3.78(4H, t), 4.87 (4H, t), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 149 —CH₂(Py4) —Bn Cl HCl 6 F: 3.94 150 —CH₂(Py3) —Bn Cl HCl 6 F: 3.94 151 —(CH₂)₂Ph —(CH₂)₂OMe Cl — 6 F: 375 152 —CH₂Th —(CH₂)₂OMe Cl — 6 F: 367 153 —CH₂Fu —(CH₂)₂OMe Cl — 6 F: 351 154 —CH₂Pyr —(CH₂)₂OMe Cl — 6 F: 363 N1: 2.8-3.2(6H, m), 3.84(2H, t), 4.92(2H, t), 6.19(2H, s), 7.8-8.0(2H, m), 8.0-8.2(2H, m), 8.52(1H, dd), 8.62(1H, d), 8.92(1H, d) 155 —CH₂Qu —(CH₂)₂OMe Cl HCl 6 F: 412 156 —(CH₂)₂(Py2) —(CH₂)₂OMe Cl HCl 6 F: 376 157 —(CH₂)₂(Py3) —(CH₂)₂OMe Cl HCl 6 F: 376 158 —(CH₂)₂(Py4) —(CH₂)₂OMe Cl HCl 6 F: 376 159 —(CH₂)₂In —(CH₂)₂OMe Cl — 6 F: 414 160 —CH₂Dio —(CH₂)₂OMe Cl — 6 F: 405 161 —(CH₂)₃Im —(CH₂)₂OMe Cl HCl 6 F: 379 N1: 2.3-2.6(2H, m), 2.98(3H, s), 3.27(3H, s), 3.79(2H, t), 4.45(2H, t), 4.76(2H, t), 4.86 (2H, t), 7.73(1H, d), 7.95(1H, d), 7.9-8.1 (2H, m), 8.1-8.3(2H, m), 9.40(1H, s), 15.14 (1H, br) 162 —(CH₂)₂Im —(CH₂)₂OMe Cl HCl 6 F: 365 N1: 2.71(3H, s), 3.26(3H, s), 3.34(2H, t), 3.79 (2H, t), 4.81(2H, t), 5.00(2H, t), 7.50(1H, s), 7.9-8.1(2H, m), 8.1-8.3(2H, m), 9.04 (1H, s), 14.76(1H, br), 15.49(1H, br) 163 —CH₂Bim —(CH₂)₂OMe Cl HCl 6 F: 401

TABLE 17 (Ic)

Ex —R¹ —R² X Sal Sy Dat 12 —(CH₂)₂CO₂H —Me Cl — — F+: 299 164 —(CH₂)₂O(CH₂)₂—NH₂ —(CH₂)₂OMe Cl HCl 6 F: 358 165 —(CH₂)₅NH₂ —(CH₂)₂OMe Cl HCl 6 F: 356 166 —(CH₂)₂O(CH₂)₂—O(CH₂)₂NH₂ —(CH₂)₂OMe Cl HCl 6 F: 402 167 —CH(Me)Ph —(CH₂)₂OMe Cl — 6 F: 375 168 —CH₂(5-MePyr) —(CH₂)₂OMe Cl — 6 F: 377 N1: 2.99(3H, s), 3.27(3H, s), 3.82(2H, t), 4.92(2H, t), 6.13(2H, s), 7.9-8.1 (2H, m), 8.1-8.3(2H, m), 8.4-8.5(1H, m), 8.7-8.9(1H, m) 169 —CH₂Pyr —CH₂Pyr Cl — 6 F: 397 N1: 3.09(3H, br), 6.24(4H, br), 7.7- 8.3(4H, m), 8.5-8.8(4H, m), 9.00(2H, d) 170 —CH₂(Py4) —CH₂Pyr Cl — 6 F: 396 N1: 2.96(3H, s), 6.11(2H, s), 6.20(2H, s), 7.3-7.5(2H, m), 7.8-8.1(2H, m), 8.0-8.2(2H, m), 8.5-8.8(4H, m), 9.01(1H, d) 171

—Me Cl HCl 6 F: 400 172

—Me Cl — 6 F: 382 173

—Me Cl — 6 F: 339 174 —(CH₂)₁₇Me —(CH₂)₂OMe Cl — 6 F: 523 175 —CH₂Ad —(CH₂)₂OMe Cl — 6 F: 421 176 —CH₂CHPh₂ —(CH₂)₂OMe Cl — 6 F: 451 177 —(CH₂)₂O(CH₂)₂—OMe —(CH₂)₂OMe Cl — 6 F: 373 N1: 2.91(3H, s), 3.15(3H, s), 3.24(3H, s), 3.3-3.4(2H, m), 3.4-3.6(2H, m), 3.79 (2H, t), 3.87(2H, t), 4.7-5.0(4H, m), 7.9- 8.1(2H, m), 8.1-8.3(2H, m) 178 —(CH₂)₂O(CH₂)₂—O(CH₂)₂OMe —(CH₂)₂OMe Cl — 6 F: 417 179 —(CH₂)₂O(4-BnO—Ph) —(CH₂)₂OMe Cl — 6 F: 497

TABLE 18 (Id)

Ex B¹ —R^(f) Sal Sy Dat 8 Py3 2-OH — — F: 378 9 Py3 6-Cl — — F: 396 N1: 2.91(3H, s), 3.25(3H, s), 3.79(2H, t), 4.86(2H, t), 6.05 (2H, s), 7.59(1H, d), 7.87(1H, dd), 7.9-8.1(2H, m), 8.1-8.3 (2H, m), 8.45(1H, d) 180 Py3 H HCl 6 F: 362 N1: 2.93(3H, s), 3.26(3H, s), 3.80(2H, t), 4.88(2H, t), 6.16 (2H, s), 7.8-8.3(6H, m), 8.7-8.9(2H, m) 181 Py2 H HCl 6 F: 362 N1: 2.98(3H, s), 3.28(3H, s), 3.84(2H, t), 4.93(2H, t), 6.17 (2H, s), 7.3-7.6(1H, m), 7.71(1H, d), 7.8-8.4(5H, m), 8.52 (1H, d) 182 Py4 H HCl 6 F: 362 N1: 2.92(3H, s), 3.28(3H, s), 3.83(2H, t), 4.92(2H, t), 6.35 (2H, s), 7.9-8.3(6H, m), 8.98(2H, d) 183 Py3 1-oxide HCl 6 F: 378 184 Py3 2-Cl HCl 6 F: 396 N1: 2.92(3H, s), 3.28(3H, s), 3.84(2H, t), 4.93(2H, t), 6.03 (2H, s), 7.3-7.6(2H, m), 7.9-8.0(2H, m), 8.0-8.3(2H, m), 8.42(1H, dd) 185 Py4 2-OH — 8 F: 378 N1: 2.84(3H, s), 3.26(3H, s), 3.81(2H, t), 4.88(2H, t), 5.84 (2H, s), 5.96(1H, s), 6.22(1H, dd), 7.44(1H, d), 7.9-8.1 (2H, m), 8.1-8.3(2H, m) 186 Py3 6-OMe HCl 6 F: 392 N1: 2.92(3H, s), 3.24(3H, s), 3.7-4.0(5H, m), 4.6-5.5(2H, m), 5.97(2H, s), 6.87(1H, d), 7.75(1H, d), 7.9-8.1(2H, m), 8.1-8.4(3H, m) 187 Py3 2-NMe₂ HCl 6 F: 405 188 Py3 6-NMe₂ HCl 6 F: 405 189 Py3 5-Me HCl 6 F: 376 190 Py3 6-Me HCl 6 F: 376 191 Py3 6-CF₃ HCl 6 F: 430 192 Py4 2-Cl HCl 6 F: 396 N1: 2.87(3H, s), 3.27(3H, s), 3.81(2H, t), 4.90(2H, t), 6.09 (2H, s), 7.3-7.5(3H, m), 7.8-8.4(4H, m), 8.45(1H, d) 193 Py4 2-NMe₂ HCl 6 F: 405

TABLE 19 (Ie)

Ex —R^(j) Sal Sy Dat 194 H — 6 F: 361 N1: 2.85(3H, s), 3.24(3H, s), 3.80(2H, t), 4.88(2H, t), 6.05 (3H, s), 7.2-7.5(5H, m), 7.9-8.3(4H, m) 195 2-Cl — 6 F: 395 196 3-Cl — 6 F: 395 197 4-Cl — 6 F: 395 N1: 2.85(3H, s), 3.24(3H, s), 3.79(2H, t), 4.86(2H, t), 6.02 (2H, s), 7.34(2H, d), 7.48(2H, d), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 198 3,4-Cl — 6 F+: 431 199 2-OMe — 6 F: 391 200 3-OMe — 6 F: 391 201 4-OMe — 6 F: 391 202 4-Ph — 6 F: 437 203 3-CN — 6 F: 386 204 4-CN — 6 F: 386 205 4-SO₂NH₂ — 6 F: 440 206 4-CF₃ — 6 F: 429 207 4-F — 6 F: 379 N1: 2.87(3H, s), 3.24(3H, s), 3.79(2H, t), 4.87(2H, t), 6.03 (2H, s), 7.1-7.6(4H, m), 7.9-8.1(2H, m), 8.1-8.3(2H, m) 208 4-Br — 6 F: 439, 441 209 3-CH₂NH₂ HCl 6 F: 390 210 4-CH₂NH₂ HCl 6 F: 390 211 3-NO₂ — 6 F: 406 212 4-NO₂ — 6 F: 406 N1: 2.87(3H, s), 3.26(3H, s), 3.81(2H, t), 4.89(2H, t), 6.18 (2H, s), 7.61(2H, d), 7.9-8.4(6H, m)

TABLE 20 (If)

Ex A —R² —R³ Sal Sy Dat 213

—Me —CH₂OMe — 6 F: 315 214

—Me —CH₂NMe₂ HCl 6 F: 328 215

—(CH₂)₄— — 6 F: 311 216

—(CH₂)₂OMe —Me — 6 F: 374 N1: 2.90(3H, s), 3.72(2H, t), 3.77 (2H, t), 4.81(2H, t), 4.87(2H, t), 8.1-8.5(3H, m) 217

—(CH₂)₂OMe —Me HCl 6 F: 330 218

—(CH₂)₂OMe —Me — 6 F: 393

TABLE 21 (Ig)

Co R¹ R² R³ 1 —CH₂CH═CH— —(CH₂)₂N(Bn)₂ Me CH₂OMe 2 —(CH₂)₂OMe —CH(Ph)CO₂Et Me 3 —(CH₂)₂OMe —(CH₂)₂SO₂NH₂ Me 4 Me —(CH₂)₂SCH₂Ph Me 5 —(CH₂)₂OMe —(CH₂)₂CO₂H Me 6 —(CH₂)₂OMe —(CH₂)₂CO(Pyr) Me 7 —(CH₂)₂OMe —(CH₂)₂CONH₂ Me 8 —(CH₂)₂OMe —(CH₂)₂— Me N[(CH₂)₂NMe₂]₂ 9 —(CH₂)₂OMe —(CH₂)₂O(CH₂)₂— Me NH(CH₂)₂NMe₂ 10 —(CH₂)₂OMe —(CH₂)₂O(Py4) Me 11 —CH₂C≡C— —(CH₂)₂— Me CH₂OMe NHCONH₂ 12 —(CH₂)₂OMe —(CH₂)₂CO₂Me Me 13 —(CH₂)₂OMe Me CF₃ 14 —CH₂(Pyr) —(CH₂)₂OMe H 15 —(CH₂)₂OMe —(CH₂)₂O— Me (CH₂)₂NMe₂ 16 —(CH₂)₂O— —(CH₂)₂OMe Me (c-Pr) 17 —(CH₂)₂OMe —(CH₂)₂OCH₂— 18 —(CH₂)₂OMe —(CH₂)₂N(Me)— Me COPh 19 Me —(CH₂)₂NO₂ Me 20 —(CH₂)₂OMe —(CH₂)₂CN Me 21 —(CH₂)₂OMe —CH₂COPh Me 22 —(CH₂)₂OMe —CH₂CONH₂ Me 23 —(CH₂)₂OMe —(CH₂)₂OAc Me 24 Me —(CH₂)₂Ac— Me 25 —(CH₂)₂NH— —(CH₂)₂— Me (CH₂)₂NH₂ N(Me)Bn 26 —(CH₂₎ ₂OMe —(CH₂)₂— Me NHSO₂Me 27 —(CH₂)₂OMe —(CH₂)₂— Me CONHOMe 28 —(CH₂)₂OMe —(CH₂)₂OCO— Me CH₂CO₂Et 29 Me —(CH₂)₂SOMe Me 30 —(CH₂)₂OMe Me c-Pr 31 Me —(CH₂)₂OMe —(CH₂)₂— OMe 32 —(CH₂)₂OMe —(CH₂)₃O— Me (CH₂)₂NMe₂ 33 —(CH₂)₂O— —(CH₂)₂OMe Me (CH₂)₂(Morp) 34 —(CH₂)₂OMe —(CH₂)₂N(Me)CH₂—

TABLE 22 (Ih)

Co R¹ R³ R⁴ 35 —CH₂(Py4) Me 7-CF₃ 36 —CH₂(Py3) Me 5-CH₂NH₂ 37 —CH₂(Pyr) H 6-NMe₂ 38 —(CH₂)₂OMe Me 5-NO₂

TABLE 23 (Ii)

Co R² R³ R⁴ 39 —CH₂(Pyr) Me 5-F 40 —CH₂(Py4) Me 6-F 41 —(CH₂)₂OMe Me 7-F 42 —CH₂(Py3) H 8-F 43 —CH₂(Pyr) Me 8-CN 44 —CH₂(Py3) Me 5-CF₃ 45 —(CH₂)₂OMe Et 6-CF₃ 46 —(CH₂)₂OMe Me 5,8-OH 47 —CH₂(Py4) Me 8-CH₂NH₂ 48 —CH₂(Py4) Me 7-Me 49 —CH₂(Py3) Me 8-Me 50 —(CH₂)₂OMe Me 7-NMe₂ 51 —CH₂(Py4) Me 8-NMe₂ 52 —CH₂(Pyr) Me 6,7-diMe 53 —CH₂(Py4) H 6-NO₂ 54 —(CH₂)₂OMe Me 5-Me 55 —CH₂(Pyr) i-Pr 6-Me 56 —(CH₂)₂OMe Me 5-CH₂NMe₂ 57 —CH₂(Py4) i-Pr 5-OMe 58 —CH₂(Py3) Me 6-OMe 59 —CH₂(Pyr) Me 7-OMe 60 —(CH₂)₂OMe Me 8-OMe 61 —CH₂(Py4) Me 5-CN 62 —CH₂(Py3) Et 6-CN 63 —(CH₂)₂OMe Me 7-CN 64 —CH₂(Pyr) Me 8-CF₃ 65 —(CH₂)₂OMe Me 5-CH₂N(Me)Bn 66 —(CH₂)₂OMe H 6-CH₂NH₂ 67 —CH₂(Pyr) Me 7-CH₂NH₂ 68 —CH₂(Py4) Me 6-Me,7-F 69 —CH₂(Py3) Me 5-NMe₂ 70 —(CH₂)₂OMe Me 5,8-OMe 71 —(CH₂)₂OMe Me 5-CH₂N(Me)COPh 72 —CH₂(Py3) Me 7-NO₂ 73 —CH₂(Pyr) Me 8-NO₂ 74 —(CH₂)₂OMe Me 5-CH₂(Morp)

TABLE 24 (Ij)

Co R¹ R² X 75 —CH₂(Pyr) —(CH₂)₂OMe Br 76 —CH₂(Py3) —(CH₂)₂OMe Br 77 —CH₂(Py4) —(CH₂)₂OMe AcO 78 —CH₂(Pyr) —(CH₂)₂OMe AcO 79 —CH₂(Py3) —(CH₂)₂OMe PhSO₃ 80 —(CH₂)₂OMe —(CH₂)₂OMe PhSO₃ 81 —CH₂(Pyr) —(CH₂)₂CO₂ ⁻ — 82 —CH₂(Py4) —(CH₂)₂CO₂ ⁻ — 83 —CH₂(Py3) —CH₂CO₂ ⁻ — 84 —(CH₂)₂OMe —CH₂CO₂ ⁻ — 85 —CH₂(Py4) —(CH₂)₂OMe I 86 —(CH₂)₂OMe —(CH₂)₂OMe I

TABLE 25 (Ik)

Co R¹ R² 87 —(CH₂)₂OMe

88

—(CH₂)₂OMe 89 —(CH₂)₂OMe

90 —(CH₂)₂OMe

91 —(CH₂)₂OMe

92 —(CH₂)₂OMe

93 —(CH₂)₂OMe

94

—(CH₂)₂OMe 95 —(CH₂)₂OMe

96 —(CH₂)₂OMe

97 —(CH₂)₂OMe

98 Me

99 —(CH₂)₂OMe

100

—(CH₂)₂OMe 101 —(CH₂)₂OMe

102 —(CH₂)₂OMe

103 Me

104

—(CH₂)₂OMe 105

—(CH₂)₂OMe 106 —(CH₂)₂OMe

107 Me

108 —(CH₂)₂OMe

109 —(CH₂)₂OMe

110 —(CH₂)₂OMe

111

Me 112 —(CH₂)₂OMe

113 —(CH₂)₂OMe

114 —(CH₂)₂OMe

115 —(CH₂)₂OMe

116

—(CH₂)₂OMe 117 Me

118 —(CH₂)₂OMe

119

—(CH₂)₂OMe 120

—(CH₂)₂OMe

TABLE 26 Co R¹ R² 121

—(CH₂)₂OMe 122 —(CH₂)₂OMe

123 —(CH₂)₂OMe

124 —(CH₂)₂OMe

125 —(CH₂)₂OMe

126 —(CH₂)₂OMe

127 —(CH₂)₂OMe

128 —(CH₂)₂OMe

129 —(CH₂)₂OMe

130

—(CH₂)₂OMe

TABLE 27 (Im)

Co R¹ R² A 131 —(CH₂)₂OMe —(CH₂)₂OMe

132 —(CH₂)₂OMe —(CH₂)₂OMe

133 —CH₂(Py3) —(CH₂)₂OMe

134 —(CH₂)₂OMe —(CH₂)₂OMe

135 —CH₂(Py3) —(CH₂)₂OMe

136 —(CH₂)₂OMe —(CH₂)₂OMe

137 —(CH₂)₂OMe —(CH₂)₂OMe

138 —(CH₂)₂OMe —(CH₂)₂OMe

139 —(CH₂)₂OMe —(CH₂)₂OMe

140 —(CH₂)₂OMe —CH₂(Pyr)

141 —(CH₂)₂OMe —(CH₂)₂OMe

142 —CH₂(Py4) —(CH₂)₂OMe

143 —(CH₂)₂OMe —(CH₂)₂OMe

144 —(CH₂)₂OMe —CH₂(Py4) 

What is claimed is:
 1. A fused imidazolium derivative represented by the following general formula (I)

(wherein symbols in the formula have the following meanings; R¹ and R²: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), group B: —OR^(a), —SR^(a), -prodrug-formed OH, —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), —O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-O-lower alkylene-NR^(a)R^(b), —O-lower alkylene-NR^(c)-lower alkylene-NR^(a)R^(b), —OCO—NR^(a)R^(b), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)—SO₂R^(b), —NR^(a)R^(b), —NR^(c)-lower alkylene-NR^(a)R^(b), —N(-lower alkylene-NR^(a)R^(b))₂, -RinD, —NO₂, —CN, -halogen, —CO₂R^(a), —COO⁻, —CONR^(a)R^(b), —CONR^(a)—O—R^(b), —NR^(a)—COR^(b), —NR^(a)—CO—NR^(b)R^(c), —OCOR^(a) and —CO—R^(a), R^(a), R^(b) and R^(c): the same or different from one another and each represents —H, -lower alkyl, -lower alkylene-RinD or -RinD, RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents), R³: —H or -(lower alkyl which may have one or more substituents), or R² and R³ may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴ (R⁴: —H or -lower alkyl), ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, and X⁻: counter anion, with the proviso that X⁻ does not exist when the substituent —COO⁻ of the group B forms intramolecular salt with imidazolium cation, with the proviso that compounds having the following combinations of R¹ and R² are excluded: (1) one is -lower alkylene-(aryl which may have one or more substituents) and the other is —CH₃, —(CH₂)₃CH₃ or -phenyl, (2) one is -lower alkylene-CO-(aryl which may have one or more substituents) and the other is —CH₂CH(CH₃)₂ or —(CH₂)₃CH₃, or (3) R¹ and R² are both -benzyl, —(CH₂)₂OC₂H₅ or —(CH₂)₂O—COCH₃.
 2. The fused imidazolium derivative according to claim 1, wherein at least one of R¹ and R² is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents selected from group C) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C); group C is -lower alkyl, -halogen, -halogeno lower alkyl, —OR^(a), —O-lower alkylene-OR^(a), —SR^(a), —NR^(a)R^(b), —NO₂, —CN, —CO₂R^(a), —CO—NR^(a)R^(b), —COR^(a), —NR^(a)—COR^(b), —SO₂NR^(a)R^(b), -lower alkylene-NR^(a)R^(b), -aryl, -lower alkylene-aryl and —OCO—R^(a); RinD is -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C), -(cycloalkyl which may have one or more substituents selected from group C), -(cycloalkenyl which may have one or more substituents selected from group C), -(aryl which may have one or more substituents selected from group C) or -(heteroaryl which may have one or more substituents selected from group C); R³ is —H or -(lower alkyl which may have one or more substituents selected from group B), or R² and R³ may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR⁴; and ring A is aryl ring which may have one or more substituents selected from group C or heteroaryl ring which may have one or more substituents selected from group C.
 3. The fused imidazolium derivative according to claim 2, wherein at least one of R¹ and R² is a lower alkyl having one or more substituents selected from group B; R³ is methyl group; and ring A is benzene ring which may have one or more substituents selected from group C or heteroaryl ring selected from thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyridine, pyrazine, pyridazine and pyrimidine rings, which may have one or more substituents selected from group C.
 4. The fused imidazolium derivative according to claim 2 or 3, wherein at least one of R¹ and R² is a lower alkyl having one or more substituents selected from the group consisting of —OR^(a), —NR^(a)R^(b), —NR^(a)—COR^(b), —O-lower alkylene-OR^(a), —O-lower alkylene-O-lower alkylene-OR^(a), —SR^(a), —CONR^(a)R^(b), —CN, -(cycloalkyl which may have one or more substituents selected from group C), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group C), -(aryl which may have one or more substituents selected from group C) and -(heteroaryl which may have one or more substituents selected from group C).
 5. The fused imidazolium derivative according to claim 2 or 3, wherein at least one of R¹ and R² is a lower alkyl having one substituent selected from the group consisting of -(heteroaryl selected from pyridyl, pyrazinyl and pyrimidinyl, which may have one or more substituents selected from group C), —O-lower alkylene-O-lower alkyl and —O-lower alkyl, and ring A is benzene ring which may be substituted by —NO₂.
 6. The fused imidazolium derivative according to claim 1, wherein it is selected from 1-[(6-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3ium, 1,2-dimethyl-4,9-dioxo-3-[(2-tetrahydrofuranyl)methyl]-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1,3-bis(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1-(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[3-(1H-4-imidazolyl)propyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-1-[(5-methyl-2-pyrazinyl)methyl]-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 2-methyl-4,9-dioxo-1,3-bis(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3ium, 1-[2-(2-methoxyethoxy)ethyl[-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(3-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(2-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(4-pyridylmethyl)-4,9-dihydro-1H-naphtho]2,3-d]imidazol-3-ium, 1-[(2-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-hydroxy-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-1-[(6-methoxy-3-pyridyl)methyl]-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-chloro-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-chlorobenzyl)-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-fluorobenzyl)-3-(2-methoxyethyl)-2methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium and 1,3-bis(2-methoxyethyl)-2-methyl-5-nitro-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium or tautomers thereof and their salts with halogen ions.
 7. A pharmaceutical composition which comprises the fused imidazolium derivative of claim 1 and a pharmaceutically acceptable carrier.
 8. The pharmaceutical composition according to claim 7, wherein it is an anticancer agent.
 9. A fused imidazole derivative represented by the following general formula (III) or a salt thereof

(wherein symbols in the formula have the following meanings; R¹: a lower alkyl having one or more substituents selected from the group consisting of —ORa, —O-lower alkylene-ORa, -lower alkylene-O-lower alkylene-ORa, -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(aryl which may have one or more substiuents selected from the group C) and -(heteroaryl which may have one or more substituents selected from the group C), with the proviso that a lower alkyl group having one or more substituents selected from the group consisting of —OH, and -(phenyl which may be substituted by —Cl, —F, —Me or —OMe) is excluded, Group C: -lower alkyl, -halogen, -halogeno lower alkyl, —OH, —O-lower alkyl, —O-lower alkylene-OH, —O-lower alkylene-O-lower alkyl, -lower alkylene-NH₂, NH₂, —NH-lower alkyl, —N (lower alkyl)₂, —CO₂H, —CO₂-lower alkyl, —CO—NH₂, —SO₂—NH₂, —NO₂ and —CN, R^(a), —H, -lower alkyl, -lower alkylene-RinD or -RinD, RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents), R³: —H or -(lower alkyl which may have one or more substituents), and ring A: benzene ring which may be substituted by —NO₂). 